1. Field of the Invention
The present invention relates to non-invasive sensing of substances such as, for example, non-invasive sensing of transcutaneous blood gases for respiratory management in patients.
2. Background of the Related Art
The Background of the Related Art and the Detailed Description of Preferred Embodiments below cite numerous technical references, which are listed in the Appendix below. The numbers shown in parenthesis at the end of some of the sentences refer to specific references listed in the Appendix. For example, a “(1)” shown at the end of a sentence refers to reference “1” in the Appendix below. All of the references listed in the Appendix below are incorporated by reference herein in their entirety.
Challenges of Preterm Birth
Optimal cellular functioning depends on an adequate supply of oxygen and acid-base balance. Highly complex biologic systems have evolved to maintain cellular functions during aberrant conditions of low and high oxygen exposures and to correct acid-base imbalance. When these systems are overwhelmed, cellular damage occurs. The fetus, which is dependent on the placenta for gas exchange, is exposed to relatively low oxygen concentrations and anti-oxidant defense mechanisms are under-developed (1).
Preterm birth requires technologies for supporting immature organ systems on the one hand, while minimizing technology-induced injury on the other that may contribute to long-term adverse outcomes. Specific problems of this kind are extremes in arterial partial pressure of oxygen (PaO2) and carbon dioxide (PaCO2). A variety of pathological conditions are known to result from both hypoxemia and hyperoxia. However, current understanding is that the range for acceptable PaO2 is quite narrow. Similarly, hypocarbia or hypercarbia can result in brain or ocular pathology. The optimal range of PaCO2 has not been established, but avoiding extremes is critical for survival.
Consequences of Hypoxia and Hyperoxia
Severe hypoxemia that can occur in utero as a result of acute or chronic placental dysfunction, or postnatally in infants with cyanotic congenital heart disease or neonatal lung disease, may cause brain injury, multi-organ failure, pulmonary hypertension, and death. Although oxygen therapy for newborns has been used in the United States since the 1930s, its relationship to retinopathy of prematurity (ROP) (previously retrolental fibroplasis), a potentially blinding disease, was not recognized until the 1950s (2). Fluctuations in arterial partial pressure of oxygen (PaO2)(i.e. swings from hypoxia to hyperoxia) also increase the risk for ROP, underscoring the need for monitoring devices that are responsive to rapid changes in PaO2 (3). Efforts to define an optimal oxygen target range to minimize the incidence of ROP continue to the present (4, 5, 6).
Pulmonary oxygen toxicity contributes to bronchopulmonary dysplasia (BPD), the major respiratory morbidity of prematurity characterized by an arrest of alveolar development (7, 8). As summarized by Finer and Leone, “the therapeutic index for oxygen use seems to be much narrower than previously realized, and we have yet to define the optimal oxygen exposure for the most premature infants” (1).
Consequences of Hypocarbia and Hypercarbia
Extremes in arterial partial pressure of carbon dioxide (PaCO2) also contribute to neonatal morbidities. Hypocarbia in the first few days of life may contribute to altered cerebral blood flow in the preterm infant. Potential consequences include intraventricular hemorrhage (IVH), periventricular leukomalacia (white matter injury), and cerebral palsy (9, 10, 11, 12). Hypocarbia resulting from overventilation contributes to volutrauma and the development of BPD (13). Permissive hypercapnea has been proposed as a strategy to limit lung injury, but the safety of this practice has not been established (14, 15, 16). Indeed, early exposure to hypercarbia and associated acidosis increases the risk for severe ROP and IVH (17, 15).
The optimal range of PaCO2 has not been established in the neonatal population, but clearly, rapid recognition of and response to extremes in PaCO2 is critical for survival and minimizing morbidities.
Status of Neonatal Blood Gas Monitoring
For the reasons discussed above, arterial blood gas (ABG) measurements are indispensable for respiratory management in the neonatal intensive care unit (NICU). Although arterial blood gas (ABG) measurements remain the gold standard for guiding respiratory management in the NICU, the necessity for placement of indwelling arterial lines or intermittent arterial or heel blood sampling are associated with potential complications such as infection, thrombus formation, bleeding, and procedure-associated pain. In addition, the frequency of blood sampling often necessitates blood transfusions to replace blood volume. Further, ABGs, at best provide only intermittent information concerning dynamic changes in blood gases.
To address these concerns, non-invasive devices have been developed to continuously monitor blood gases. In the 1970s, transcutaneous monitors were developed to measure the amount of O2 (tcPO2) and CO2 (tcCO2) dissolved in tissue that approximated arterial values when the skin underneath the sensor was heated to 43-44° C. (18). Disadvantages included the potential for skin burns, necessitating frequent sensor site changes and re-calibration. Accuracy was affected by skin thickness, peripheral perfusion, and use of vasopressors (18).
Since its introduction in the 1980s, pulse oximetry, which measures the proportion of hemoglobin in arterial blood that is bound to oxygen, has largely replaced tcPO2 monitors in most NICUs. Pulse oximeters are easy to use, and do not require heating the skin or calibration. However, false alarms may occur due to motion artifacts. In addition, due to the shape of the hemoglobin-oxygen dissociation curve, small changes in oxygen saturation (SpO2)>95% can fail to detect large increases in PaO2, thus limiting the usefulness of pulse oximetry for detection of hyperoxia (19). In addition, compared to SpO2 monitoring, tcPO2 monitoring was associated with less variability in oxygen tension and greater proportion of time spent within the oxygen target range (19).
TcPCO2 monitoring is more accurate than end-tidal CO2 monitors in patients with shunt or ventilation/perfusion inequalities, and can be used in situations such as high frequency or non-invasive ventilation where ET-CO2 cannot (20). Recently, a SpO2/tcPCO2 combination sensor and a neonatal sized tcO2/tcPCO2 combination sensor based on current technology have been introduced (21, 22).
To address some of the above concerns, transcutaneous monitors for O2 (tcpO2) and CO2 (tcCO2) using electrochemical sensors have been used. However, these electrodes have at least the following disadvantages: (1) they suffer from calibration drift due to depletion of the electrolyte; (2) they lack sensitivity at low O2 due to consumption of O2 by the Clark electrode; (3) the potential for membrane failure; (4) the use of adhesives to maintain direct skin contact; and (5) the possibility of burns from raising skin temperature to 43° C. for tcpO2 monitoring. The last two issues, in particular, can lead to serious skin injury. Given the drawbacks of current technologies, it is clear that a new generation of neonatal monitoring devices is needed that is: (1) non-invasive/painless; (2) more accurate and sensitive than current sensors; (3) easy to use by staff; and (4) and can follow dynamic changes in blood gases for longer periods of time.